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【结 构 式】 
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【分子编号】10059 【品名】Ethylene bromohydrin; 2-Bromo-1-ethanol 【CA登记号】540-51-2 |
【 分 子 式 】C2H5BrO 【 分 子 量 】124.9651 【元素组成】C 19.22% H 4.03% Br 63.94% O 12.8% |
合成路线1
该中间体在本合成路线中的序号：(A)Compound can be prepared in two similar ways both starting from 7-chloro-1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepin-2-one-4-oxide (I): 1) The condensation of (I) with 2-bromoethanol (A) by means of NaH in DMF gives the N-hydroxyethyl derivative (II), which by refluxing with acetic anhydride is converted into 7-chloro-1,3-dihydro-1-(2-acetoxyethyl)-3-acetoxy-5-(o-fluorophenyl)-2H-1,4-benzodiazepin-2-one (III). Finally, (III) is deacetylated with methanolic ammonia. 2) The condensation of (I) with 2-bromoethylacetate (B) as before gives the N-acetoxyethyl derivative (IV), which by refluxing with acetic anhydride is converted into (III).
| 【1】 Tamagnone, G.F.; et al.; A new benzodiazepine: 1-(2-hydroxyethyl)-3-hydroxy-7-chloro-1,3-dihydro-5-(o-fluorophenyl)-2H-1,4-benzodiazepine-2-one. J Pharm Pharmacol 1974, 26, 566. |
| 【2】 De Marchi, F.; Tamagnone, G.F.; Benzodiazepine compounds for therapeutical use. DE 2338058; ES 405260; FR 2194432; GB 1431282; JP 49080086 . |
| 【3】 Tamagnone, G.F.; et al.; A new series of benzodiazepines: 1-Hydroxyalkyl derivatives of 1,3-dihydro-2H-1,4-benzodiazepin-2-one. Arzneim-Forsch Drug Res 1975, 25, 5, 720-722. |
| 【4】 de Angelis, L.; Castaner, J.; SAS-643. Drugs Fut 1978, 3, 2, 145. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (B) | 33463 | 2-bromoethyl acetate | 927-68-4 | C4H7BrO2 | 详情 | 详情 |
| (I) | 33459 | 7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-4-ium-4-olate | C15H10ClFN2O2 | 详情 | 详情 | |
| (II) | 33460 | 7-chloro-5-(2-fluorophenyl)-1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-4-ium-4-olate | C17H14ClFN2O3 | 详情 | 详情 | |
| (III) | 33461 | 2-[3-(acetoxy)-7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]ethyl acetate | C21H18ClFN2O5 | 详情 | 详情 | |
| (IV) | 33462 | 1-[2-(acetoxy)ethyl]-7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-4-ium-4-olate | C19H16ClFN2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)A new synthesis of fleroxacin, labeled with fluorine-18, has been described: The reaction of 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (I) with 2-bromoethanol (II) gives 6,7,8-trifluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (III), which is condensed with N-methylpiperazine (IV), yielding 6,8-difluoro-1-(2-hydroxyethyl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (V). The reaction of (V) with methanesulfonyl chloride affords the corresponding mesylate (VI), which is treated with [18F]-KF in dichloromethane at 80 C to give 6,8-difluoro-1-(2-fluoroethyl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (VII). Finally, this compound is hydrolyzed with NaOH.
| 【1】 Liu, Y.Y.; Cleeland, R.; Livni, E.; Rubin, R.H.; Thom, E.; Strauss, H.W.; Fischman, A.J.; Fleroxacin, a quinolone antibacterial agent. Labeling with fluorine-18 for pharmacokinetic studies. J Label Compd Radiopharm 1993, 32, 576. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10058 | ethyl 6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | 79660-46-1 | C12H8F3NO3 | 详情 | 详情 |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 10060 | ethyl 6,7,8-trifluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C14H12F3NO4 | 详情 | 详情 | |
| (IV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (V) | 10062 | ethyl 6,8-difluoro-1-(2-hydroxyethyl)-7-(4-methylpiperazino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C19H23F2N3O4 | 详情 | 详情 | |
| (VI) | 10063 | ethyl 6,8-difluoro-7-(4-methylpiperazino)-1-[2-[(methylsulfonyl)oxy]ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C20H25F2N3O6S | 详情 | 详情 | |
| (VII) | 10064 | ethyl 6,8-difluoro-1-(2-fluoroethyl)-7-(4-methylpiperazino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C19H22F3N3O3 | 详情 | 详情 | |
| (VII) | 44571 | ethyl 6,8-difluoro-1-(2-fluoroethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C19H22F3N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)A new synthesis of [14C]-labeled E-1040 with the label in the quinuclidine ring has been reported: The reduction of [14C]-labeled bromoacetic acid (I) with borane-dimethyl sulfide complex in ethyl ether gives 2-bromoethanol (II), which is condensed with piperidine-4-carboxamide (III) by means of K2CO3 and KI in refluxing isopropanol, yielding the [14C]-labeled 1-(2-hydroxyethyl)piperidine-4-carboxamide (IV). The reaction of (IV) with SOCl2 in refluxing acetonitrile affords the 1-(2-chloroethyl)piperidine-4-carbonitrile (V), which is cyclized by means of lithium diisopropylamide in THF, giving the quinuclidine (VI). The hydrolysis of (VI) with sulfuric acid gives [14C]-labeled quinuclidine-4-carboxamide (VII), which is finally condensed with the 3-chloromethylcephalosporin (VIII) by means of Na in acetone and a treatment with trifluoroacetic acid.
| 【1】 Woolley, G.T.; Sugiyama, I.; Yamauchi, H.; Mizuo, H.; Synthesis of 14C-labelled cefclidin (E1040). J Label Compd Radiopharm 1992, 31, 9, 663. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (I) | 45074 | 2-bromoacetic acid | C2H3BrO2 | 详情 | 详情 | |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 45075 | 2-bromo-1-ethanol | C2H5BrO | 详情 | 详情 | |
| (III) | 11762 | 4-Piperidinecarboxamide; Isonipecotamide | 39546-32-2 | C6H12N2O | 详情 | 详情 |
| (IV) | 11763 | 1-(2-Hydroxyethyl)-4-piperidinecarboxamide | C8H16N2O2 | 详情 | 详情 | |
| (IV) | 45076 | 1-(2-hydroxyethyl)-4-piperidinecarboxamide | C8H16N2O2 | 详情 | 详情 | |
| (V) | 11764 | 1-(2-Chloroethyl)-4-piperidinecarbonitrile | C8H13ClN2 | 详情 | 详情 | |
| (V) | 45077 | 1-(2-chloroethyl)-4-piperidinecarbonitrile | C8H13ClN2 | 详情 | 详情 | |
| (VI) | 11765 | 4-Quinuclidinecarbonitrile | C8H12N2 | 详情 | 详情 | |
| (VI) | 45078 | 4-quinuclidinecarbonitrile | C8H12N2 | 详情 | 详情 | |
| (VII) | 11766 | 4-Quinuclidinecarboxamide | C8H14N2O | 详情 | 详情 | |
| (VII) | 45079 | 4-quinuclidinecarboxamide | C8H14N2O | 详情 | 详情 | |
| (VIII) | 11767 | 4-methoxybenzyl (6R,7R)-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C21H21ClN6O6S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The reaction of diketene (I) with 2-bromoethanol (II) by means of dimethylaminopyridine (DMAP) in dichloromethane gives acetoacetic acid 2-bromoethyl ester (III), which is condensed with 3-nitrobenzaldehyde (IV) by means of piperidine acetate in isopropanol yielding the corresponding 3-nitrobenzylidene derivative (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) by heating at 80 C affords 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-bromoethyl) 5-methyl diester (VII), which is condensed with chloromethyl ethyl ether (VIII) by means of NaH in THF to afford the corresponding 1-ethoxymethyl derivative (IX). The reaction of diester (IX) with NaCN and tetrabutylammonium cyanide or sodium p-toluenesulfonate and benzyltriethylammonium chloride (BTEACl) in DMF gives 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (X). The optical resolution of (X) through the cinchonidine salt yields, after crystallization, the cinchonidine salt of the (R)-enantiomer (XI), which is treated with HCl to eliminate the cinchonidine, and esterified with 1,3-dibromopropane and K2CO3 in acetone to afford (R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(3-bromopropyl) 5-methyl diester (XII). Finally, this compound is condensed with 4,4-diphenylpiperidine (XIII) by means of K2CO3 in DMF at 100 C.
| 【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Dexniguldipine hydrochloride. Drugs Fut 1997, 22, 2, 114. |
| 【2】 Amschler, H.; Flockerzi, D.; Klemm, K.; Kohl, B.; Eistetter, K.; Eltze, M.; Kolassa, N.; Sanders, K.; Schudt, C. (Byk Gulden Lomberg Chemische Fabrik GmbH); 1,4-Dihydropyridine enantiomers. AU 8816264; EP 0296316; EP 0343193; WO 8807525 . |
| 【3】 Klemm, K.; Ulrich, W.-R.; Flockerzi, D.; Sanders, K.; Beller, K.-D. (Byk Gulden Lomberg Chemische Fabrik GmbH); Optically pure (R)-(-)-niguldipine and its derivs. for treating tumor diseases. WO 8907443 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 13144 | 2-bromoethyl 3-oxobutanoate | C6H9BrO3 | 详情 | 详情 | |
| (IV) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 13146 | 2-bromoethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C13H12BrNO5 | 详情 | 详情 | |
| (VI) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VII) | 63539 | 3-(2-bromoethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C18H19BrN2O6 | 详情 | 详情 | |
| (VIII) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (IX) | 13150 | 3-(2-bromoethyl) 5-methyl 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H25BrN2O7 | 详情 | 详情 | |
| (X) | 13151 | 1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (XI) | 12671 | (4S)-1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (XII) | 13153 | 3-(3-bromopropyl) 5-methyl (4R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H21BrN2O6 | 详情 | 详情 | |
| (XIII) | 13154 | 4,4-Diphenylpiperidine | C17H19N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)This compound has been obtained by several related ways: 1) The reaction of ethyl butyrylacetate (I) with triethyl orthoformate and Ac2O gives acrylate (II), which by reaction with o-toluidine (III) yields the aminoacrylate (IV). The cyclization of (IV) by heating at 255 C in diphenyl ether affords the quinolone (V), which is treated with refluxing POCl3 to give 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (VI). The demethylation of (VI) with AlCl3 or BBr3 yields the 8-hydroxyquinoline (VII), which is condensed with o-toluidine (VIII) in refluxing dioxane affording 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX). Finally, this compound is condensed with 2-bromomethanol (X) by means of potassium tert-butoxide or with ethylene carbonate (XI) by means of K2CO3. 2) The condensation of chloroquinoline (VI) with o-toluidine (VIII) in refluxing dioxane gives 1-[8-methoxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (XII), which is demethylated with AlCl3 or BBr3 as before yielding the previously reported 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX).
| 【1】 Atkins, R.J.; et al.; Synthetic routes to quinoline derivatives: Novel syntheses of 3-butyryl-8-methoxy-4-[(2-methylphenyl)amini]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quin. Org Process Res Dev 1997, 1, 3, 185. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 | |
| (I) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (II) | 12517 | ethyl (E)-2-butyryl-3-ethoxy-2-propenoate | C11H18O4 | 详情 | 详情 | |
| (III) | 25193 | 2-methoxyphenylamine; 2-methoxyaniline | 517-28-2 | C7H9NO | 详情 | 详情 |
| (IV) | 12518 | ethyl (Z)-2-butyryl-3-(2-methoxyanilino)-2-propenoate | C16H21NO4 | 详情 | 详情 | |
| (V) | 12519 | 3-Butyryl-8-methoxy-4(1H)-quinolinone | C14H15NO3 | 详情 | 详情 | |
| (VI) | 12520 | 1-(4-Chloro-8-methoxy-3-quinolinyl)-1-butanone | C14H14ClNO2 | 详情 | 详情 | |
| (VII) | 32800 | 1-(4-chloro-8-hydroxy-3-quinolinyl)-1-butanone | C13H12ClNO2 | 详情 | 详情 | |
| (VIII) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (IX) | 32801 | 1-[8-hydroxy-4-(2-toluidino)-3-quinolinyl]-1-butanone | C20H20N2O2 | 详情 | 详情 | |
| (X) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (XI) | 32802 | 1,3-dioxolan-2-one | 96-49-1 | C3H4O3 | 详情 | 详情 |
| (XII) | 32799 | 1-[8-methoxy-4-(2-toluidino)-3-quinolinyl]-1-butanone | C21H22N2O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Alkylation of 3,4-dichlorophenylacetonitrile (VI) with (tetrahydropyranyloxy)ethyl bromide (V) (prepared by protection of 2-bromoethanol (IV) with dihydropyran) furnished nitrile (VII). Catalytic hydrogenation of (VII) in the presence of Raney-Ni and Et3N gave the primary amine (VIII). After acidic hydrolysis of the tetrahydropyranyl group of (VIII), the resultant amino alcohol was resolved by means of D-tartaric acid providing the (S)-enantiomer (IX). Reaction of amine (IX) with ethyl chloroformate afforded carbamate (X), which was further reduced to the N-methyl amine (XI) employing LiAlH4. Subsequent acylation of (XI) with benzoyl chloride furnished benzamide (XII). Mesylate (XIII) was then prepared by treatment of alcohol (XII) with methanesulfonyl chloride and triethylamine. Finally, condensation between piperidine (III) and mesylate (XIII) led to the title compound
| 【1】 Emonds-Alt, X.; Goulaouic, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Arylalkylamines, process for their preparation and pharmaceutical compsns. containing them. EP 0474561; FR 2666335; FR 2678267; JP 1992261155; US 5236921; US 5350852 . |
| 【2】 Emonds-Alt, X.; Proietto, V.; Van Broeck, D.; Vilain, P.; Advenier, C.; Neliat, G.; Le Fur, G.; Breliere, J.-C.; Pharmacological profile and chemical synthesis of SR 48968, a non-peptide antagonist of the neurokinin A (NK2) receptor. Bioorg Med Chem Lett 1993, 3, 5, 925. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 59283 | N-(4-phenyl-4-piperidinyl)acetamide | C13H18N2O | 详情 | 详情 | |
| (IV) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (V) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (VI) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (VII) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (VIII) | 26937 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (IX) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (X) | 26940 | ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate | C13H17Cl2NO3 | 详情 | 详情 | |
| (XI) | 26941 | (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol | C11H15Cl2NO | 详情 | 详情 | |
| (XII) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XIII) | 62380 | (3S)-4-(benzoylamino)-3-(3,4-dichlorophenyl)butyl methanesulfonate | C18H19Cl2NO4S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The intermediate N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate (IV) was prepared by an improved procedure consisting of addition of phosphoryl chloride to 2-bromoethanol (I) in the presence of Et3N, followed by in situ treatment of the resulting intermediate (II) with bis(2-chloroethyl)amine (III).
| 【1】 Lyttle, M.H.; et al.; Glutathione-S-transferase activates novel alkylating agents. J Med Chem 1994, 37, 10, 1501. |
| 【2】 Kauvar, L.; Lyttle, M.H.; Satyam, A. (Telik, Inc.); Glutathione S-transferase-activated cpds.. WO 9509866 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 13033 | Dichlorophosphoric acid 2-bromoethyl ester | C2H4BrCl2O2P | 详情 | 详情 | |
| (III) | 21583 | 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine | 821-48-7 | C4H9Cl2N | 详情 | 详情 |
| (IV) | 46425 | C10H20BrCl4N2O2P | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The alkylation of 2-(3,4-dimethoxyphenyl)ethylamine (I) with 2-bromoethanol (II) provides the bis(hydroxyethyl) amine (III). Subsequent chlorination of diol (III) with SOCl2 affords the corresponding bis(chloroethyl) amine (IV). This is finally cyclized with 3-phenylpropylamine (V) to furnish the title piperazine derivative, which is isolated as the dihydrochloride salt.
| 【1】 Kawashima, Y.; Matsumoto, J.; Matsuno, K.; Senda, T.; Hirano, K. (Santen Pharmaceutical Co., Ltd.); Novel 1,4-di(phenylalkyl)piperazine deriv.. EP 0711763; JP 1995089949; US 5736546; WO 9504050 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 57495 | 2-[(3,4-dimethoxyphenethyl)(2-hydroxyethyl)amino]-1-ethanol | C14H23NO4 | 详情 | 详情 | |
| (IV) | 57496 | N,N-bis(2-chloroethyl)-N-(3,4-dimethoxyphenethyl)amine; 2-chloro-N-(2-chloroethyl)-N-(3,4-dimethoxyphenethyl)-1-ethanamine | C14H21Cl2NO2 | 详情 | 详情 | |
| (V) | 18791 | 3-phenylpropylamine; 3-phenyl-1-propanamine | 2038-57-5 | C9H13N | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Alkylation of 4-(demethoxy)daunorubicin (I) with 2-bromoethanol (II) affords the hydroxyethyl amine (III). This is treated with methanesulfonyl chloride and diisopropyl ethylamine to produce the bis-mesylate (IV). Cyclization of (IV) to the title aziridino derivative is then accomplished by treatment with silicagel or with diisopropyl ethylamine.
| 【1】 Fontana, E.; Felicini, C.; Synthesis of PNU-159548 labelled with 14C and 2H. J Label Compd Radiopharm 2002, 45, 7, 543. |
| 【2】 Bargiotti, A.; Caruso, M.; Grandi, M.; Ripamonti, M.; Suarato, A. (Pharmacia AB); 3'-Aziridino-anthracycline derivs.. EP 0683788; JP 1996506835; US 5532218; WO 9516695 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 57492 | (7S,9S)-9-acetyl-7-{[(4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-6,9,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C26H27NO9 | 详情 | 详情 | |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 57493 | (7S,9S)-9-acetyl-6,9,11-trihydroxy-7-({(4S,5S,6S)-5-hydroxy-4-[(2-hydroxyethyl)amino]-6-methyltetrahydro-2H-pyran-2-yl}oxy)-7,8,9,10-tetrahydro-5,12-naphthacenedione | C28H31NO10 | 详情 | 详情 | |
| (IV) | 57494 | (2S,3S,4S)-6-{[(1S,3S)-3-acetyl-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy}-2-methyl-4-({2-[(methylsulfonyl)oxy]ethyl}amino)tetrahydro-2H-pyran-3-yl methanesulfonate | C30H35NO14S2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)The reaction of 2-bromoethanol (I) with dihydropyran by means of a strong acid ion exchange resin gives the tetrahydropyranyl ether (II), which is condensed with 2-(3,4-dichlorophenyl)acetonitrile (III) by means of NaH in THF yielding thebutyronitrile (IV). The reduction of (IV) with H2 over RaNi in ethanol/NH4OH affords the butylamine (V), which is deprotected with HCl in methanol providing racemic 2-(3,4-dichlorophenyl)-4-hydroxybutylamine (VI). The optical resolution of (VI) with D-tartaric acid affords the corresponding (S) isomer (VII), which is treated with ethyl chloroformate and triethylamine in dichloromethane to give the carbamate (VIII). The reduction of (VIII) with LiAlH4 in THF yields N-[2(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylamine (IX), which is acylated with benzoyl chloride (X) and triethylamine in dichloromethane to affords the amide (XI). Oxidation of the hydroxyl group of (XI) with Dess-Martin periodinane yields the corresponding aldehyde (XII), which is reductocondensed with 4-[N-(trifluoroacetyl)-N-[3-(trifluoroacetamido)propyl]amino]piperidine (XIII) by means of NaBH3CN in methanol/acetic acid providing the bis(trifluoroacetylated) intermediate (XIV). The deprotection of (XIV) with KOH in methanol/water gives the diamine intermediate (XV), which is finally cyclized with carbonyldiimidazole (CDI) in chloroform.
| 【1】 Miller, S.C. (AstraZeneca plc); Therapeutic heterocycles which antagonize neurokinin receptors. JP 1997501439; US 5567700; US 5990130; US 6124279; WO 9505377 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 26935 | 2-(3,4-dichlorophenyl)acetonitrile | 3218-49-3 | C8H5Cl2N | 详情 | 详情 |
| (IV) | 26936 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C15H17Cl2NO2 | 详情 | 详情 | |
| (V) | 26937 | 2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C15H21Cl2NO2 | 详情 | 详情 | |
| (VI) | 26938 | 4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (VII) | 26939 | (3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol | C10H13Cl2NO | 详情 | 详情 | |
| (VIII) | 26940 | ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate | C13H17Cl2NO3 | 详情 | 详情 | |
| (IX) | 26941 | (3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol | C11H15Cl2NO | 详情 | 详情 | |
| (X) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XI) | 26942 | N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide | C18H19Cl2NO2 | 详情 | 详情 | |
| (XII) | 26943 | N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide | C18H17Cl2NO2 | 详情 | 详情 | |
| (XIII) | 26944 | 2,2,2-trifluoro-N-(4-piperidinyl)-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]acetamide | C12H17F6N3O2 | 详情 | 详情 | |
| (XIV) | 26945 | N-[(2S)-2-(3,4-dichlorophenyl)-4-[4-((2,2,2-trifluoroacetyl)[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino)-1-piperidinyl]butyl]-N-methylbenzamide | C30H34Cl2F6N4O3 | 详情 | 详情 | |
| (XV) | 26946 | N-[(2S)-4-[4-[(3-aminopropyl)amino]-1-piperidinyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide | C26H36Cl2N4O | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)A new synthesis of (9S)-9-(hydroxymethyl)-6,7,10,11- tetrahydro-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20-dione (XI), a key intermediate in the synthesis of LY-333531, has been reported: Enantiocontrolled condensation of 2-bromoethanol (I) with epoxide (II) by means of a chiral Pd catalyst, triethylborane and DMAP in dichloromethane gives the chiral allyl ether (III), which is protected with TIPS-OTf yielding the silyl ether (IV). Hydroboration of ether (IV) with 9-BBN followed by oxidation with H2O2 provides the primary alcohol (V), which is mesylated with MsCl to afford the mesylate (VI). Mesylate (VI) is cyclized with the bisindolylmaleimide (VII) by means of Cs2CO3 in DMF at 100 C resulting in the macrocyclic compound (VIII). Hydrolysis of (VIII) with KOH, followed by acidic workup yields the anhydride (IX), which by treatment with HMDS in methanolic DMF provides the maleimide (X). Finally, this compound is desilyl-ated with TBAF to afford the target intermediate (XI).
| 【1】 Trost, B.M.; Tang, W.; An enantioselective strategy to macrocyclic bisinsolylmaleimides, an efficient formal synthesis of LY 333531. Org Lett 2001, 3, 21, 3409. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 32805 | 2-vinyloxirane | 930-22-3 | C4H6O | 详情 | 详情 |
| (III) | 53241 | (2S)-2-(2-bromoethoxy)-3-buten-1-ol | n/a | C6H11BrO2 | 详情 | 详情 |
| (IV) | 53242 | {[(2S)-2-(2-bromoethoxy)-3-butenyl]oxy}(triisopropyl)silane; (2S)-2-(2-bromoethoxy)-3-butenyl triisopropylsilyl ether | n/a | C15H31BrO2Si | 详情 | 详情 |
| (V) | 53243 | (3S)-3-(2-bromoethoxy)-4-[(triisopropylsilyl)oxy]-1-butanol | n/a | C15H33BrO3Si | 详情 | 详情 |
| (VI) | 53244 | (3S)-3-(2-bromoethoxy)-4-[(triisopropylsilyl)oxy]butyl methanesulfonate | n/a | C16H35BrO5SSi | 详情 | 详情 |
| (VII) | 53245 | 1-benzyl-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione | n/a | C27H19N3O2 | 详情 | 详情 |
| (VIII) | 53246 | (18S)-4-benzyl-18-{[(triisopropylsilyl)oxy]methyl}-17-oxa-4,14,21-triazahexacyclo[19.6.1.1~7,14~.0~2,6~.0~8,13~.0~22,27~]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione | n/a | C42H49N3O4Si | 详情 | 详情 |
| (IX) | 53247 | (18S)-18-{[(triisopropylsilyl)oxy]methyl}-4,17-dioxa-14,21-diazahexacyclo[19.6.1.1~7,14~.0~2,6~.0~8,13~.0~22,27~]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione | n/a | C35H42N2O5Si | 详情 | 详情 |
| (X) | 53248 | (18S)-18-{[(triisopropylsilyl)oxy]methyl}-17-oxa-4,14,21-triazahexacyclo[19.6.1.1~7,14~.0~2,6~.0~8,13~.0~22,27~]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione | n/a | C35H43N3O4Si | 详情 | 详情 |
| (XI) | 41013 | (18S)-18-(hydroxymethyl)-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione | C26H23N3O4 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)Protection of 2-bromoethanol (I) upon treatment with 2-methoxypropene (II) gave a mixture of ketals (III) and (IV). This mixture was used for N-alkylation of 5-bromoindole (V) in the presence of KOH to afford, after ketal hydrolysis, 1-(2-hydroxyethyl)-5-bromoindole (VI) (1). Alternatively, compound (VI) was obtained by alkylation of 5-bromoindole (V) with ethylene oxide (VII) in the presence of NaOH in DMSO (2). The hydroxyl group of (VI) was then protected as the silyl ether (VII) by treatment with tert-butyldimethylsilyl chloride. Subsequent lithium-halogen exchange in (VIII) with tert-butyllithium, followed by reaction with bismuth trichloride provided the triindolyl bismuthane (IX) (1, 2). This was oxidized with either benzoyl peroxide (1) or peracetic acid (2) to produce the corresponding di(acyloxy) pentavalent bismuthanes (X).
| 【1】 Brands, K.M.J.; et al.; Mild aryl ether formation in the semisynthesis of the novel macrolide immunosuppressant L-732,531. J Org Chem 1998, 63, 19, 6721. |
| 【2】 Sinclair, P.J.; Goulet, M.; Wong, F.; Parsons, W.H.; Goulet, J.; Wyvratt, M.J. (Merck & Co., Inc.); O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroaryl macrolides. EP 0532088; JP 1994116274; US 5252732; WO 9305058 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Xa) | 26858 | 2-[5-(bis(acetoxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]]-lambda(5)-bismuthanyl)-1H-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether | C52H78BiN3O7Si3 | 详情 | 详情 | |
| (Xb) | 26859 | 2-[5-(bis(benzoyloxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]]-lambda(5)-bismuthanyl)-1H-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether | C62H82BiN3O7Si3 | 详情 | 详情 | |
| (I) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (III) | 26853 | 2-(2-bromoethoxy)-2-methoxypropane | C6H13BrO2 | 详情 | 详情 | |
| (IV) | 26854 | 1-(2-bromoethoxy)-1-methylethyl 2-bromoethyl ether | C7H14Br2O2 | 详情 | 详情 | |
| (V) | 13309 | 5-Bromo-1H-indole; 5-Bromoindole | 10075-50-0 | C8H6BrN | 详情 | 详情 |
| (VI) | 26855 | 2-(5-bromo-1H-indol-1-yl)-1-ethanol | C10H10BrNO | 详情 | 详情 | |
| (VII) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (VIII) | 26856 | 2-(5-bromo-1H-indol-1-yl)ethyl tert-butyl(dimethyl)silyl ether | C16H24BrNOSi | 详情 | 详情 | |
| (IX) | 26857 | 2-(5-[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]bismuthino]-1H-indol-1-yl)ethyl tert-butyl(dimethyl)silyl ether | C48H72BiN3O3Si3 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(V)In a different method, amine (I) was alkylated with 2-bromoethanol (V) to give the N-(hydroxyethyl) amine (VI), which was further converted to bromo amine (VII) by treatment with concentrated HBr. Friedel-Crafts cyclization of (VII) upon heating in the presence of AlCl3 furnished tetrahydroisoquinoline (IV).
| 【1】 Lee, Y.N.; Hong, Y.W.; Kim, H.B. (Yuhan Corp.); Process for preparation of pyrmidine derivs.. US 5990311; WO 9742186 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (IV) | 54971 | 1-methyl-1,2,3,4-tetrahydroisoquinoline | C10H13N | 详情 | 详情 | |
| (V) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (VI) | 54972 | 2-[(1-phenylethyl)amino]-1-ethanol | C10H15NO | 详情 | 详情 | |
| (VII) | 54973 | N-(2-bromoethyl)-1-phenyl-1-ethanamine; N-(2-bromoethyl)-N-(1-phenylethyl)amine | C10H14BrN | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(VI)Condensation between aminomalononitrile (I) and benzyl isocyanate (II) produces imidazole (III). This is then cyclized with benzoyl isothiocyanate (IV) in the presence of NaOH to furnish the mercaptopurine derivative (V). Finally, alkylation of thiol (V) with 2-bromoethanol (VI) gives rise to the target hydroxyethyl sulfide.
| 【1】 Kawakami, H.; Ogino, T.; Kurimoto, A. (Japan Energy Corp.; Sumitomo Pharmaceuticals Co., Ltd.); Novel heterocyclic cpds.. EP 1035123; US 6329381; WO 9928321 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 63650 | 2-aminomalononitrile | C3H3N3 | 详情 | 详情 | |
| (II) | 16730 | 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate | 3173-56-6 | C8H7NO | 详情 | 详情 |
| (III) | 63651 | 5-amino-1-benzyl-2-hydroxy-1H-imidazole-4-carbonitrile | C11H10N4O | 详情 | 详情 | |
| (IV) | 23530 | benzoyl isothiocyanate | 532-55-8 | C8H5NOS | 详情 | 详情 |
| (V) | 63652 | 6-amino-9-benzyl-2-sulfanyl-9H-purin-8-ol | C12H11N5OS | 详情 | 详情 | |
| (VI) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(II)The precursor bromoether (III) was prepared by condensation of 4,4’-difluorobenzhydrol (I) with 2-bromoethanol (II) under acidic conditions. Treatment of 4-bromocinnamic acid (IV) with thionyl chloride afforded acid chloride (V), which was coupled with ethylenediamine (VI) to furnish mono amide (VII). The title compound was finally obtained by alkylation of amine (VII) with bromide (III) in the presence of K2CO3.
| 【1】 Elmaleh, D.R.; Fischman, A.J.; Hanson, R.N.; Choi, S.-W.; Design, synthesis, and biological evaluation of novel non-piperazine analogues of 1-[2-(diphenylmethoxy]ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]4-(3-phenylpropyl)piperazines as dopamine transporter inhibitors. J Med Chem 1999, 42, 18, 3647. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 41974 | 4,4'-Difluorobenzhydrol; bis(4-Fluorophenyl)methanol; alpha-(4-fluorophenyl)benzenemethanol; 4-fluoro-alpha-(4-fluorophenyl)benzenemethanol | 365-24-2 | C13H10F2O | 详情 | 详情 |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 41975 | 1-[(2-bromoethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene; bis(4-fluorophenyl)methyl 2-bromoethyl ether | C15H13BrF2O | 详情 | 详情 | |
| (IV) | 41976 | (E)-3-(4-bromophenyl)-2-propenoic acid | C9H7BrO2 | 详情 | 详情 | |
| (V) | 41977 | (E)-3-(4-bromophenyl)-2-propenoyl chloride | C9H6BrClO | 详情 | 详情 | |
| (VI) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (VII) | 41978 | (E)-N-(2-aminoethyl)-3-(4-bromophenyl)-2-propenamide | C11H13BrN2O | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(A)4,7-Dihydroxy-8-methylcoumarin (I) was selectively protected as the monosilylated derivative (II) using tert-butyldiphenylsilyl chloride and Et3N. Subsequent Mitsunobu coupling of (II) with 2-bromoethanol (A) produced the bromoethoxy coumarin (III). After desilylation of (III) with a mixture of HF and KF, the resulting phenol (IV) was coupled with noviose triol (V) under Mitsunobu conditions to afford the alpha-glycoside (VI) as the major isomer. Esterification of (VI) with 5-methylpyrrole-2-carboxylic anhydride (VII) in the presence of CoCl2 yielded the desired 3'-ester (VIII) along with minor amounts of 2'-ester, which was separated by column chromatography. Finally, displacement of the bromide of (VIII) by 2-mercaptoimidazole (IX) furnished the corresponding thioether.
| 【1】 Ferroud, D.; Laurin, P.; Schio, L.; et al.; Structure-activity relationship in two series of aminoalkyl substituted coumarin inhibitors of gyrase B. Bioorg Med Chem Lett 1999, 9, 19, 2875. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (I) | 40543 | 4,7-dihydroxy-8-methyl-2H-chromen-2-one | C10H8O4 | 详情 | 详情 | |
| (II) | 40544 | 7-[[tert-butyl(diphenyl)silyl]oxy]-4-hydroxy-8-methyl-2H-chromen-2-one | C26H26O4Si | 详情 | 详情 | |
| (III) | 40545 | 4-(2-bromoethoxy)-7-[[tert-butyl(diphenyl)silyl]oxy]-8-methyl-2H-chromen-2-one | C28H29BrO4Si | 详情 | 详情 | |
| (IV) | 40546 | 4-(2-bromoethoxy)-7-hydroxy-8-methyl-2H-chromen-2-one | C12H11BrO4 | 详情 | 详情 | |
| (V) | 40547 | (3R,4S,5R)-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2,3,4-triol | C8H16O5 | 详情 | 详情 | |
| (VI) | 40548 | 4-(2-bromoethoxy)-7-[[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-8-methyl-2H-chromen-2-one | C20H25BrO8 | 详情 | 详情 | |
| (VII) | 40549 | 5-methyl-1H-pyrrole-2-carboxylic anhydride | C12H12N2O3 | 详情 | 详情 | |
| (VIII) | 40550 | (3R,4S,5R,6R)-6-[[4-(2-bromoethoxy)-8-methyl-2-oxo-2H-chromen-7-yl]oxy]-5-hydroxy-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl 5-methyl-1H-pyrrole-2-carboxylate | C26H30BrNO9 | 详情 | 详情 | |
| (IX) | 34456 | 1H-imidazole-2-thiol; 1H-imidazol-2-ylhydrosulfide | 872-35-5 | C3H4N2S | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(A)Dihydroartemisinin (II) was prepared by NaBH4 reduction of artemisinin (I). Condensation of (II) with 2-bromoethanol (A) in the presence of boron trifluoride etherate yielded the 10beta-bromoethyl acetal (III). Finally, reaction of (III) with dimethylamine in DMF provided the desired amine, which was finally converted to the oxalate salt.
| 【1】 Pan, J.-P.; Jiang, H.-J.; Wu, J.-M.; Zhu, Y.-M.; Wu, G.-S.; Li, Y.; Synthesis and antimalarial activity of artemisinin derivatives containing an amino group. J Med Chem 2000, 43, 9, 1635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (A) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (I) | 22369 | Qinghaosu; Artemisine; (1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-one | 63968-64-9 | C15H22O5 | 详情 | 详情 |
| (II) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (III) | 40705 | (1R,4S,5R,8S,9R,10S,12R,13R)-10-(2-bromoethoxy)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane; 2-bromoethyl (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadec-10-yl ether | C17H27BrO5 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(II)Condensation of 4,4'-dichlorobenzhydrol (I) with 2-bromoethanol (II) in the presence of sulfuric acid gave the bromopropyl ether (III), which was further condensed with 2-mercaptoethanol (IV), yielding thioether (V). Subsequent coupling of alcohol (V) with methyl 3-(4-hydroxyphenyl)propionate (VI) under Mitsunobu conditions furnished adduct (VII). Basic hydrolysis of the methyl ester function generated acid (VIII). After conversion of (VIII) to the corresponding acid chloride, its condensation with trifluoroacetic anhydride gave rise to the trifluoromethyl ketone (IX). The sulfide group of (X) was finally oxidized to the title sulfone using meta-chloroperbenzoic acid.
| 【1】 Banville, J.; Burke, J.R.; Gai, Y.; Johnson, G.; Zusi, F.C. (Bristol-Myers Squibb Co.); Selective cPLA2 inhibitors. EP 1140791; WO 9915129 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 50505 | 4,4'-Dichlorobenzhydrol; Bis(4-chlorophenyl)carbinol | 90-97-1 | C13H10Cl2O | 详情 | 详情 |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 50506 | 1-[(2-bromoethoxy)(4-chlorophenyl)methyl]-4-chlorobenzene; bis(4-chlorophenyl)methyl 2-bromoethyl ether | C15H13BrCl2O | 详情 | 详情 | |
| (IV) | 36375 | 2-Sulfanyl-1-ethanol; 2-Mercaptoethanol | 60-24-2 | C2H6OS | 详情 | 详情 |
| (V) | 50507 | 2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)-1-ethanol | C17H18Cl2O2S | 详情 | 详情 | |
| (VI) | 30341 | methyl 3-(4-hydroxyphenyl)propanoate; 4-Hydroxyphenylpropionic acid methyl ester; 3-(4-Hydroxyphenyl)propionic acid methyl ester | 5597-50-2 | C10H12O3 | 详情 | 详情 |
| (VII) | 50508 | methyl 3-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]propanoate | C27H28Cl2O4S | 详情 | 详情 | |
| (VIII) | 50509 | 3-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]propionic acid | C26H26Cl2O4S | 详情 | 详情 | |
| (IX) | 50510 | 4-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone | C27H25Cl2F3O3S | 详情 | 详情 |